Inflammatory Mediator Related Diseases often result from excessive activation of the inflammatory response. The inflammatory response consists of the interaction of various cell systems (e.g., monocyte/macrophage, neutrophil, and lymphocytes) and various humoral systems (e.g., cytokines, coagulation, complement, and kallikrein/kinin). Each component of each system may function as an effector (e.g., killing pathogens, destroying tissue, etc.), a signal (e.g., most cytokines), or both. Humoral elements of the inflammatory response are known collectively as inflammatory mediators. Inflammatory mediators include various cytokines (e.g., tumor necrosis factor (“TNF”); the interleukins; interferon, etc.), various prostaglandins (e.g., PG I2, E2, Leukotrienes), various clotting factors (e.g., platelet activating factor (“PAF”)), various peptidases, reactive oxygen metabolites, and various poorly understood peptides which cause organ dysfunction (e.g., myocardial depressant factor (“MDF”)). These compounds interact as a network with the characteristics of network preservation and self-amplification. Some of these compounds, such as MDF and peptidases, are directly injurious to tissue; other compounds, such as cytokines, coordinate destructive inflammation.
The systemic inflammatory response with its network of systems (e.g., monocytes/macrophages, complement, antibody production, coagulation, kallikrein, neutrophil activation, etc.) is initiated and regulated through the cytokine system and other inflammatory mediators. (Cytokines are generally thought of as a subgroup of inflammatory mediators.) The cytokine system consists of more than 200 known molecules each of which activates or suppresses one or more components of the immune system or one or more other cytokines in the network. The cytokine network is the dominant control system of the immune response. The primary sources of cytokines are monocytes/macrophages, endothelial cells, and similar cells.
Key characteristics of the cytokine system are as follows: (i) cytokines are chemical signals coordinating immune system and associated systemic activities; (ii) commonly, two or more cytokines will trigger the same action providing a “fail safe” response to a wide variety of different stimuli (the systemic inflammatory response is critical to the individual's survival; these redundant control signals assure a systemic response which does not falter); (iii) cytokine and inflammatory mediator concentrations (usually measured in blood) therefore increase in order to stimulate, control, and maintain the inflammatory response proportionally to the severity of the injury or infection; and (iv) as severity of injury or infection increases, the cytodestructive activity of the system increases. Therefore, high concentrations of cytokines and inflammatory mediators measured in the patient's blood, that are sustained over time correlate with the patient's risk of death.
The general strategy of most treatments is to identify what is conceived to be a key or pivotal single cytokine or inflammatory mediator. This single target cytokine or inflammatory mediator is then inactivated in an attempt to abate the inflammatory response. The most widely applied technologies used to inactivate cytokines or inflammatory mediators is binding with monoclonal antibodies or specific antagonists. Monoclonal antibodies and specific antagonists are used because they effectively bind the target cytokines or inflammatory mediators, or their receptors, usually in an “all or none” blockade.
This strategy is problematic for two reasons. First, the cytokine system is essential to mobilize the inflammatory response, and through it, the host immune response. If the cytokine system were blocked, death would ensue from unhealed injury or infection. Second, the cytokine and inflammatory mediator signals which make up the control network of the immune response consist of many redundant control loops to assure the “fail safe” initiation and continuation of this critical response. Such a redundant, self-amplifying system is generally not effectively controlled by blocking one point, such as one cytokine or inflammatory mediator.
Patients with life threatening illness are cared for in hospitals in the intensive care unit. These patients may be seriously injured from automobile accidents, etc., have had major surgery, have suffered a heart attack, or may be under treatment for serious infection, cancer, or other major disease. While medical care for these primary conditions is sophisticated and usually effective, a significant number of patients in the ICU will not die of their primary disease. Rather, a significant number of patients in the ICU die from a secondary complication known commonly as sepsis or septic shock. Medically, sepsis and septic shock and their effects are sometimes referred to as Systemic Inflammatory Response Syndrome, Multiple Organ System Dysfunction Syndrome, Multiple Organ System Failure, and Compensatory Anti-inflammatory Response Syndrome.
In short, medical illness, trauma, complication of surgery, and any human disease state, if sufficiently injurious to the patient, may elicit Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure or Compensatory Anti-inflammatory Response Syndrome. The systemic inflammatory response within certain physiologic limits is beneficial. As part of the immune system, the systemic inflammatory response promotes the removal of dead tissue, healing of injured tissue, detection and destruction of cancerous cells as they form, and mobilization of host defenses to resist or to combat infection.
When stimulated by injury or infection, the systemic inflammatory response may cause symptoms which include fever, increased heart rate, and increased respiratory rate. This symptomatic response constitutes Systemic Inflammatory Response Syndrome. If the stimulus to the systemic inflammatory response is very potent, such as massive tissue injury or major microbial infection, then the inflammatory response is can be excessive. This excessive response can cause injury or destruction to vital organ tissue and may result in vital organ dysfunction, which may be manifested in many ways, including a drop in blood pressure, deterioration in lung function, reduced kidney function, and other vital organ malfunction. This condition is known as Multiple Organ System Dysfunction Syndrome. With very severe or life threatening injury or infection, the inflammatory response is extreme and can cause extensive tissue damage with vital organ damage and failure. These patients will usually die promptly without the use of ventilators to maintain lung ventilation, drugs to maintain blood pressure and strengthen the heart, and, in certain circumstances, artificial support for the liver, kidneys, coagulation, brain and other vital systems. This condition is known as Multiple Organ System Failure. These support measures partially compensate for damaged and failed organs, they do not cure the injury or infection or control the extreme inflammatory response which causes vital organ failures.
In recent years, it is increasingly recognized that Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure/Compensatory Anti-inflammatory Response Syndrome exists in phases. In particular, an early pro-inflammatory phase, which is recognized as Systemic Inflammatory Response Syndrome, usually occurs within hours or a very few days of significant injury or infection; Compensatory Anti-inflammatory Response Syndrome occurs later. Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome may also appear in repeating and alternate cycles, or concurrently.
As noted previously, the pro-inflammatory response is critical to host recovery and survival (by healing injury and eliminating infection), but when extreme this response causes vital organ dysfunction or failure. In biology, it is common for one response to be counter balanced by another response; these compensatory responses or systems allow restoration of balance and return the organism (e.g., the patient) to homeostasis. Compensatory Anti-inflammatory Response Syndrome is associated with the abatement of the excesses inflammatory mediators characteristic of Systemic Inflammatory Response Syndrome, however Compensatory Anti-inflammatory Response Syndrome itself is often extreme and results in immune suppression. Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome are each associated with respective characteristic inflammatory mediators. The immune suppression of Compensatory Anti-inflammatory Response Syndrome is very commonly associated with secondary infection. This secondary infection then elicits another Systemic Inflammatory Response Syndrome, often worse and more destructive than the first. In patients, it is commonly this second episode of Systemic Inflammatory Response Syndrome which is lethal.
Both Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome are mediated by excesses of either pro-inflammatory and anti-inflammatory mediators, respectively. Hemofiltration may be as beneficial to Compensatory Anti-inflammatory Response Syndrome as to Systemic Inflammatory Response Syndrome. However, in Systemic Inflammatory Response Syndrome the improvement may be affirmatively observed by improvement in pulmonary and cardio-circulatory function and survival, whilst in Compensatory Anti-inflammatory Response Syndrome it may be observed negatively, by non-occurrence of secondary infection and secondary Systemic Inflammatory Response Syndrome. Both Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome may be monitored in a limited way, by monitoring their respective inflammatory mediators in blood, lung fluid or other body fluid. Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory response Syndrome may occur concurrently as a mixed or an overlapping disorder.
In the United States of America each year, Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure afflicts approximately 700,000 patients and results in about 200,000 deaths. Overall, depending on the number of organ systems failing, the mortality rate of Multiple Organ System Failure ranges generally from 40 to 100%. For instance, if three or more vital organs fail, death results in about 90% of cases. Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure and Compensatory Anti-inflammatory Response Syndrome are the most common cause of death in intensive care units and are the thirteenth most common cause of death in the United States of America. Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure and Compensatory Anti-inflammatory Response Syndrome costs about $15 billion yearly for supportive care. In addition, the incidence of Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure and Compensatory Anti-inflammatory Response Syndrome are on the rise; reported cases increased about 139% between 1979 and 1987. This increase is due to an aging population, increased utilization of invasive medical procedures, immuno-suppressive therapies (e.g. cancer chemotherapy) and transplantation procedures.
Inflammatory Mediator Related Diseases include both acute problems, as well as chronic problems.
Chronic inflammatory diseases of the joints and skin such as lupus, fibromyalgia, pemphigoid and rheumatoid arthritis and other rheumatoid conditions generally result from chromic inflammation. These diseases may therefore benefit from ultrafiltration to remove their inflammatory mediators. Removal of redundant mediators may be particularly helpful.
Chronic degenerative disease of the nervous system may be mediated by abnormal levels of serum and cerebrospinal fluid antibodies. For example, abnormal levels of antibodies have been detected in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy. The immune response has also been implicated in multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosis, and cryobulinemic vasculitis. Patients with chronic degenerative diseases of the nervous system may, therefore, benefit from ultrafiltration of the blood to lower antibody levels, control inflammation or lower levels of other abnormal proteins or substances correlated with a particular degenerative neuromuscular disease.
Existing techniques of hemofiltration have been developed as a technique to control overhydration and acute renal failure in unstable ICU patients. Existing hemofiltration techniques may use a hemofilter of various designs and materials. For example, the material may consist of a cellulose derivative or synthetic membrane (e.g., polysulfone, polyamide, etc.) fabricated as either a parallel plate or hollow fiber filtering surface. Because the blood path to, through, and from the membrane is low resistance, the patient's own blood pressure drives blood through the filter circuit. In these hemofiltration applications, the hemofilter is part of a blood circuit. In passive flow hemofiltration, arterial blood flows through a large bore cannula, into plastic tubing leading to the filter; blood returns from the filter through plastic tubing to a vein. This is known as arteriovenous hemofiltration. Alternatively a blood pump is used, so that blood is pumped from either an artery or a vein to the filter and returned to a vein. This is known as pumped arteriovenous hemofiltration or pumped venovenous hemofiltration. Ultrafiltrate collects in the filter jacket and is drained through the ultrafiltrate line and discarded. Ultrafiltrate flow rates are usually 250 ml-2000 ml/hour. In order to prevent lethal volume depletion, a physiologic and isotonic replacement fluid is infused into the patient concurrently with hemofiltration at a flow rate equal to or less than the ultrafiltrate flow rate. The balance of replacement fluid and ultrafiltrate is determined by the fluid status of the patient.
Treatment of certain diseases by filtration of blood is well established medical practice. Dialysis, using dialysis filters, which remove molecules with molecular weights up to 5,000 to 10,000 Dalton, is used to treat chronic and some acute renal failure. Conventional hemofiltration, discussed below, is used to treat acute renal failure, and in some cases, chronic renal failure. Plasmapheresis, using plasma filters or centrifuge techniques which remove molecules with molecular weights of 1,000,000 to 5,000,000 Dalton or more, is used to treat diseases associated with high molecular weight pathologic immunoglobulins or immune complexes, (e.g., multiple myeloma, lupus vasculitis, etc.).
During filtration of protein-containing solutions, colloids or suspensions, or blood, the accumulation of protein as a gel or polarization layer occurs on the membrane surface. This gel layer typically reduces effective pore size, reducing the filterable molecular weights by roughly 10-40%. Therefore, pore sizes selected are somewhat larger than needed, anticipating a reduction in effective size. Thus, present membranes allow filtration and removal of excess water, electrolytes, small molecules and nitrogenous waste while avoiding loss of albumin or larger proteins. These membranes are well-suited to their accepted uses, that is, treatment of overhydration and acute renal failure in unstable ICU patients.
Observations in ICU patients indicate that hemofiltration, in addition to controlling overhydration and acute renal failure, is associated with improvements in lung function and cardiovascular function. None of these improvements has been associated with shortened course of ventilator therapy, shortened ICU stay, or improved survival. The usual amount of ultrafiltrate taken in the treatment of overhydration and acute renal failure is 250 to 2000 ml/hour, 24 hours a day. A few published observations have suggested that higher amounts of ultrafiltrate brought about greater improvements in pulmonary and cardiovascular status; these have resulted in the development of a technique known as high volume hemofiltration. In high volume hemofiltration, from 2 to 9 liters/hour of ultrafiltrate are taken for periods of from 4 to 24 hours or more.
There is however great hesitance to use high volume hemofiltration for the following reasons: (i) the high volumes (currently 24-144 liters/day) of ultrafiltrate require equally high volumes of sterile, pharmaceutical grade replacement fluid; at these high volumes, errors in measuring ultrafiltrate coming out and replacement fluid flowing into the patient could cause injurious or lethal fluid overload or volume depletion; (ii) the high volume of ultrafiltrate removed could filter out of the blood desirable compounds from the patient resulting in dangerous deficiencies; (iii) large volumes of warm (body temperature) ultrafiltrate flowing out of the patient, and large volumes of cool (room temperature) replacement fluid flowing into the patient can cause thermal stress or hypothermia; and (iv) high volumes of replacement fluid add considerable expense to the therapy.
High volume hemofiltration, as currently practiced, uses conventional hemofilters with pore sizes which provide a molecular weight cut off of 30,000 Daltons and occasionally of 50,000 Daltons. The device and process described in U.S. Pat. No. 5,571,418 generally contemplates the use of large pore hemofiltration membranes with pore sizes to provide molecular weight exclusion limits of 100,000 to 150,000 Daltons. With these higher molecular weight cutoffs, these membranes are designed to remove a wider range of different inflammatory mediators; these large pore membranes should remove excess amounts of all known inflammatory mediators. These large pore hemofiltration membranes have been demonstrated in animal studies to be superior to conventional hemofilter membranes in improving survival time in a swine model of lethal Staphylococcus aureus infection (Lee, P A et al. Critical Care Medicine April 1998). However, it may be anticipated that in high volume hemofiltration, the large pore membranes may also remove more desirable compounds thus increasing the risk of the negative side effects of high volume hemofiltration.
Other techniques used in the past to treat inflammatory diseases include hemodialysis and plasmapheresis. Hemodialysis is well suited to fluid and small solute (less the 10,000 Daltons) removal. However hemodialysis membranes remove very few inflammatory mediators (only those smaller than 5000 to 10,000 Daltons) and so have been ineffective in improving patient condition in Systemic Inflammatory Response Syndrome/Multiple Organ Dysfunction Syndrome/Multiple Organ System Failure. In the unstable ICU patient, hemodialysis commonly results in rapid deterioration of cardiovascular function and pulmonary function requiring premature termination of the dialysis procedure. Hemodialysis has also been associated with increasing the occurrence of chronic renal failure in survivors of Systemic Inflammatory Response Syndrome/Multiple Organ Dysfunction Syndrome/Multiple Organ System Failure. Hemofiltration was specifically developed to avoid these complications of hemodialysis and has been very successful in doing so.
Plasmapheresis can be done with both membrane based and centrifugation based techniques. Plasmapheresis separates plasma and all that plasma contains from blood, leaving only formed elements. The removed plasma is usually replaced by either albumin solution or fresh frozen plasma. The removed plasma would contain all inflammatory mediators. However all desirable substances, many adapted to the patient's current condition, are also removed, often with injurious or lethal effects.
Consequently, the additional methods for treatment of Inflammatory Mediator Related Diseases are needed. Furthermore, while high volume hemofiltration holds some promises, it is unworkable in its present form and is overly dangerous.